PHARMACOLOGICAL STUDIES ON THE ORPHAN OPIOID RECEPTOR IN CENTRAL AND PERIPHERAL SITES

We have exploited the availability of the ''orphan'' opioid receptor ( referred to here as ORL1) in its ''natural state'' to investigate the effect of nociceptin (orphanin FQ), the endogenous agonist for the ORL 1 receptor in the brain, vas deferens, and myenteric plexus of the sma ll intestine. Nociceptin was a potent agonist in electrically stimulat ed preparations of vasa deferentia (rat and rabbit) and myenteric plex us (guinea-pig) (IC50 ranging from 18 to 31 nM) and susceptible to enz ymic cleavage as addition of a cocktail of peptidase inhibitors to the organ bath produced a leftward shift in concentration-response curves (IC50 ranging from 2.1 to 4.9 nM). In radioligand binding experiments using brain membranes from rat, rabbit, and guinea-pig, [H-3]nocicept in bound a single population of binding sites with high affinity (K-D values ranging from 0.049 to 0.124 nM) and capacity (B-max ranging fro m 143 to 254 fmol.mg(-1) protein). However, the response to nociceptin in functional studies and in radioligand binding inhibitory assays wa s resistant to antagonism/displacement by naloxone and a range of othe r opioid receptor antagonists, thus displaying a very different pharma cological profile from that of the ''classical'' opioids. Therefore, w e conclude that the effect of nociceptin in these studies is not via a n action at mu, delta, or kappa opioid receptors but rather at an orph an opioid receptor, ORL1.